Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1- phosphatidylinositol 3-kinase complex

By Y. Zhong, Q. Wang, Xianting Li, Ying Yan, J. Backer, Brian T. Chait, N. Heintz, Zhenyu Yue. Nature Cell Biology, 2009

1,010 citations recorded by the source corpus.

Beclin 1, a mammalian autophagy protein that has been implicated in development, tumour suppression, neurodegeneration and cell death, exists in a complex with Vps34, the class III phosphatidylinositol-3-kinase (PI(3)K) that mediates multiple vesicle-trafficking processes including endocytosis and autophagy. However, the precise role of the Beclin 1–Vps34 complex in autophagy regulation remains to be elucidated. Combining mouse genetics and biochemistry, we have identified a large in vivo Beclin 1 complex containing the known proteins Vps34, p150/Vps15 and UVRAG, as well as two newly identified proteins, Atg14L (yeast Atg14-like) and Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein). Characterization of the new proteins revealed that Atg14L enhances Vps34 lipid kinase activity and upregulates autophagy, whereas Rubicon reduces Vps34 activity and downregulates autophagy. We show that Beclin 1 and Atg14L synergistically promote the formation of double-membraned organelles that are associated with Atg5 and Atg12, whereas forced expression of Rubicon results in aberrant late endosomal/lysosomal structures and impaired autophagosome maturation. We hypothesize that by forming distinct protein complexes, Beclin 1 and its binding proteins orchestrate the precise function of the class III PI(3)K in regulating autophagy at multiple steps.

Subfields: Cell Biology, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/6cbb58080729e0d4dd524d4fea9bcf1bd4f7d3c9

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

In Epidemiology

In Physiology

Citations in the corpus

Autophagy and autophagy-related proteins in cancer (2020, background): “starvation, hypoxia [27], some small molecular compounds [28], oxidation, and pathogen invasion [3, 29], a large number of autophagy is induced by the transduction of cellular signaling pathways, and many important autophagy-related proteins and their complex involved in the autophagic process [30].”
ULK1 induces autophagy by phosphorylating Beclin-1 and activating Vps34 lipid kinase (2013, methodology): “Active GST-ULK1 (1-649) and GST-ULK2 (1-478) from insect cells was purchased from CQuential Solutions (Moraga, CA).”
Molecular definitions of autophagy and related processes (2017, neutral): “…(PI3KR4; best known as VPS15) (Kihara et al , 2001a, b), the sensor of membrane curvature ATG14 (also known as ATG14L or BARKOR) (Itakura et al , 2008; Sun et al , 2008; Matsunaga et al , 2009; Zhong et al , 2009; Fan et al , 2011), and nuclear receptor binding factor 2 (NRBF2) (Lu et al , 2014a).”
Autophagy, Immunity, and Microbial Adaptations (2009, background): “…(Figure 1C), including several modifier components: (1) Atg14, which plays a role in initiation (Itakura et al., 2008; Matsunaga et al., 2009; Zhong et al., 2009), and (2) UVRAG/ VPS38, which plays a role in maturation (Itakura et al., 2008; Liang et al., 2008) and is negatively regulated by…”
The regulation of autophagy – unanswered questions (2011, background): “Atg14L (yeast Atg14-like) (Matsunaga et al., 2009; Zhong et al., 2009), activating molecule in beclin-1-regulated autophagy (AMBRA1) (Di Bartolomeo et al.”
TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation (2012, neutral): “…adaptors (Bjørkøy et al., 2005; Thurston et al., 2009; Wild et al., 2011) and the less understood process of the maturation of autophagic organelles into autolysosomes, where the captured material is degraded (Korolchuk et al., 2011; Liang et al., 2008; Matsunaga et al., 2009; Zhong et al., 2009).”